The present invention relates to analysis systems and methods thereof, and in particular to a method for detecting the presence or absence of a gas bubble in an aqueous liquid.
For the purposes of clinical diagnosis analysing systems are used for blood-gas analysis or for other measurements in liquid samples. Such systems are employed for instance for the determination of the partial pressure of oxygen or of carbon dioxide in blood, or of the hemoglobin parameters of whole blood, and for measurement of pH-value or ion concentration or special metabolites.
Complex analysis systems of this kind are usually provided with different sensor elements for determination of the parameters of interest, which elements are used for a multitude of measurements. Such sensor elements are for instance electrochemical or optical sensors for the determination of gas values, of the pH-value, of ion values or metabolite values, or optical measuring units for the determination of hemoglobin values.
In electrochemical gas sensors, also known as gas-selective or gas-sensitive electrodes, the gas molecules to be determined diffuse from an usually aqueous exterior solution or a gas phase into the interior electrolyte chamber of the sensor via a gas-permeable but essentially fluid- and ion-impermeable membrane. In addition to a liquid or solid interior electrolyte layer, the interior electrolyte chamber contains electrodes for electrochemical determination of the gas, especially measuring or working electrodes, counter-electrodes and reference electrodes. In the interior electrolyte chamber the electrochemical reactions for the determination of the gas by means of amperometric or potentiometric methods take place.
In the case of optical-chemical sensors a number of widely differing design variants and measurement principles have become known. In contrast to electrochemical sensors optical sensors do not require a reference electrode. An optical-chemical sensor typically consists of one or more layers of inorganic and/or organic, typically polymeric, substances applied on a transparent substrate, where at least one layer contains a dye whose optical properties (e.g., absorption, luminescence, etc.) are dependent on an analyte contained in the sample medium.
A frequently used gas sensor is the Clark oxygen sensor, for instance, where a gas-permeable membrane separates the interior electrolyte solution from the aqueous exterior medium, i.e., the medium to be measured. In the simplest case two electrodes dip into the interior electrolyte solution, one of which is placed immediately behind the membrane as a working electrode. After a polarization voltage of suitable strength has been applied, the oxygen which has diffused through the membrane from the measurement medium into the interior electrolyte chamber, is consumed by electrochemical reduction at the working electrode and an electric current corresponding to the substance consumed flows. This current is proportional to the partial pressure of oxygen in the medium to be measured and represents the primary measurement quantity.
Other frequently employed electrochemical gas sensors with gas-permeable membranes are for instance potentiometric sensors of the Severinghaus type for the measurement of carbon dioxide or electrochemical sensors for the determination of hydrogen by means of oxidation on platinum electrodes.
Such electrochemical gas sensors are often used in medical and diagnostic analyzers for the determination of partial gas pressures or gas concentrations in liquids. In particular, they are employed in blood gas analyzers, which play an important role in medical diagnostics. Blood gas analyzers often are provided with a plurality of sensors for diverse parameters, which are arranged in series. The sample fluid flows through these sensors, measurement often being taken by the “stop-flow-method”, i.e., with the sample at standstill during the measurement proper. Systems of this type are often used for routine measurements in clinics, laboratories and by medical practitioners, thus requiring the sensors used to have long service life, high accuracy and good reproducibility.
For the determination of oxygen in the OMNI® analyzer systems of Roche Diagnostics GmbH (Graz, Austria), for example, amperometric O2-sensors and potentiometric CO2-sensors are used. The oxygen sensors are miniaturized gas sensors of the Clark type. These gas sensor elements comprise, besides the actual sensor with its interior electrolytic chamber containing the electrodes, a sample passage for the transport and intermediate storage of the sample. Between the interior electrolytic chamber and the sample passage there is a gas-permeable and essentially ion- and fluid-impermeable plastic membrane separating the interior electrolytic chamber from the sample passage. The membrane is provided in a mechanically stretched state.
Frequently thin plastic membranes are employed in electro-chemical gas sensors, with layer thicknesses in the micrometer range, which are made from hydrophobic plastic materials, especially from polytetrafluoroethylene, polypropylene and polyethylene. Further details concerning typical membrane materials may be found in “Measurement of Oxygen by Membrane-covered Probes” (Ellis Horwood series in analytical chemistry, 1988, Ellis Horwood Limited, page 91f).
When gaseous analytes are determined in aqueous solutions by means of electrochemical gas sensors, especially in physiological fluids such as whole blood, serum or urine, problems may occur in certain rare cases during sample measurement or during calibration or quality control, if the sample or the calibrating or control medium does not completely fill the sample passage or if the solution contains gas bubbles, e.g., air bubbles, in the region of the sensors. Especially in blood-gas analyzer systems with sensor elements for small sample volumes gas bubbles may cause measurement errors, which will necessitate efficient checking for the presence or absence of gas bubbles in this case. Gas bubbles mostly adhere to the membrane surface. This phenomenon is observed when during the filling process of the sample passage the aqueous fluid avoids the hydrophobic surface of the membrane on one or both sides. If it is possible for the front of the fluid to laterally bypass the membrane before it is completely covered by the fluid, a gas bubble will form in the area of the membrane. Already existing as well as newly formed gas bubbles will mostly adhere to the membrane and will often not be removed by the fluid flow. A gas bubble adhering to the membrane or remaining in the immediate vicinity of the membrane will result in a measurement error, which will not be recognized as such without additional efforts to detect such bubbles.
The problem of enclosed air bubbles, which cause measurement errors by impeding sufficient wetting of the surface of the sensors used, is pointed out in the prior art. Measures for recognition of such errors will be necessary above all in automated analyzers, where the filling process of the measuring capillary or the absence of bubbles in the sample must be controlled automatically.
Certain known methods cannot efficiently detect air bubbles, however, which do not extend over the whole cross-section of the measuring passage or the measuring capillary. Resistance measurement would in such cases show slight variations in the measurement signal, which however could not be discerned from variations in the signal caused by different conductivity of the individual samples due to differing hematocrit values, for instance.